- Timothy syndrome
Name = PAGENAME
DiseasesDB = 34006
OMIM = 601005
Timothy syndrome is a rare
autosomal dominantdisorder characterized by physical malformations, as well as neurological and developmental defects, including heart QT-prolongation, heart arrhythmias, structural heart defects, syndactyly(webbing of fingers and toes) and autismspectrum disorders.
Timothy syndrome often ends in early death.
igns and symptoms
The most striking sign of Timothy syndrome is the co-occurrence of both
syndactyly(~0.03% of births) and long QT syndrome(1% per year) in a single patient. Other common symptoms of Timothy syndrome are cardiac arrhythmia(94%), heart malformations (59%), autismor an autism spectrum disorder (80% who survive long enough for evaluation). Facial dysmorphologies such as flattened noses also occur in approximately half of patients. Children with this disorder have small teeth which, due to poor enamel coating, are prone to dental cavitiesand often require removal. The average age of death due to complications of these symptoms is 2.5 years.cite journal | author = Marks M, Whisler S, Clericuzio C, Keating M | title = A new form of long QT syndrome associated with syndactyly | journal = J Am Coll Cardiol | volume = 25 | issue = 1 | pages = 59–64 | year = 1995 | pmid = 7798527 | doi = 10.1016/0735-1097(94)00318-K] cite journal | author = Marks M, Trippel D, Keating M | title = Long QT syndrome associated with syndactyly identified in females | journal = Am J Cardiol | volume = 76 | issue = 10 | pages = 744–5 | year = 1995 | pmid = 7572644 | doi = 10.1016/S0002-9149(99)80216-1] cite journal | author = Splawski I, Timothy K, Sharpe L, Decher N, Kumar P, Bloise R, Napolitano C, Schwartz P, Joseph R, Condouris K, Tager-Flusberg H, Priori S, Sanguinetti M, Keating M | title = Ca(V)1.2 calcium channel dysfunction causes a multisystem disorder including arrhythmia and autism | journal = Cell | volume = 119 | issue = 1 | pages = 19–31 | year = 2004 | pmid = 15454078 | doi = 10.1016/j.cell.2004.09.011]
Atypical Timothy syndrome has largely the same symptoms as the classical form. Differences in the atypical form are the lack of syndactyly, the presence of musculoskeletal problems (particularly hyperflexible joints), and
atrial fibrillation. Patients with atypical Timothy syndrome also have more facial deformities, including protruding foreheads and tongues. Finally, one patient with atypical Timothy syndrome had body development discrepancy wherein her upper body was normally developed (that of a 6 year old) while her lower half resembled a 2 or 3 year old.cite journal | author = Splawski I, Timothy K, Decher N, Kumar P, Sachse F, Beggs A, Sanguinetti M, Keating M | title = Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations | journal = Proc Natl Acad Sci U S A | volume = 102 | issue = 23 | pages = 8089–96; discussion 8086–8 | year = 2005 | pmid = 15863612 | doi = 10.1073/pnas.0502506102]
Syndactyly and other deformities are typically observed and diagnosed at birth. Long QT syndrome sometimes presents itself as a complication due to surgery to correct syndactyly. Other times, children collapse spontaneously while playing. In all cases it is confirmed with
ECGmeasurements. Sequencing of the CACNA1C gene further confirms the diagnosis.
There are two recognized types of Timothy syndrome, classical (type-1) and atypical (type-2). They are both caused by mutations in CACNA1C, the gene encoding the
calcium channelCav1.2 α subunit. Timothy syndrome mutations in CACNA1C cause delayed channel closing and, thus, increased cellular excitability.
Both classical and atypical Timothy syndromes are caused by
mutations in CACNA1C. These mutations are in exon 8 (atypical form) and exon 8a (classical form), a alternatively spliced exon. Exon 8a is highly expressed in the heart, brain, gastrointestinal system, lungs, immune system and smooth muscle. Exon 8 is also expressed in these regions and its level is approximately 5-fold higher than exon 8a expression.
There is one mutation found in patients with classical Timothy syndrome, G406R, located just past the 6th membrane spanning segment of domain 1 (D1S6). The conserved
glycineat this position seems to be vital for proper voltage dependent inactivation as the mutant is lacking in this respect. Atypical Timothy syndrome mutations are similar, one being the identical G406R mutation in the other splice form and the second mutation being G402S, located a few amino acids upstream. The affect of these mutations on channel function is identical to the G406R mutation in classical Timothy syndrome. The lack of proper voltage-dependent inactivation in these mutants causes prolonged inward current and depolarizationduring cardiac action potentials. This leads to long QT syndromeand resultant arrhythmia. It should be noted that because exon 8 has greater expression in the heart versus exon 8a, patients with atypical Timothy syndrome have worsened cardiac defects compared to those with the classical form.
Surgery is typically used to correct structural heart defects and syndactyly.
Propanololor beta-adrenergic blockers are often prescribed as well as insertion of a pacemaker to maintain proper heart rhythm. With the characterization of Timothy syndrome mutations indicating that they cause defects in calciumcurrents, it has been suggested that calcium channelblockers may be effective as a therapeutic agent.
The prognosis for patients diagnosed with Timothy syndrome is grim. Of 17 children analyzed in one study, 10 died at an average age of 2.5 years. Of those that did survive, 3 were diagnosed with
autism, one with an autism spectrum disorder, and the last had severe delays in language development. One patient with atypical Timothy syndrome was largely normal with the exception of heart arrhythmia. Likewise, the mother of two Timothy syndrome patients also carried the mutation but lacked any obvious phenotype. In both of these cases, however, the lack of severity of the disorder was due to mosaicism.
Timothy disorder was named in honor of Dr. Katherine W. Timothy, who was among the first to identify a case of severe
long QT syndromeand syndactylyand performed much of the phenotypic analysis that revealed other abnormalities.
* [http://focus.hms.harvard.edu/2004/Oct15_2004/genetics.html Article at focus.hms.harvard.edu]
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